Effect of integrated hepatitis C virus treatment on psychological distress in people with substance use disorders

People with substance use disorders (SUD) have a high prevalence of chronic hepatitis C virus (HCV) infection and mental health disorders. We aimed to assess the impact of integrated HCV treatment on psychological distress measured by Hopkins-symptom-checklist-10 (SCL-10). This multi-center randomized controlled trial evaluated psychological distress as a secondary outcome of integrated HCV treatment (INTRO-HCV trial). From 2017 to 2019, 289 participants were randomly assigned to receive either integrated or standard HCV treatment with direct-acting antiviral therapy. Integrated HCV treatment was delivered in eight decentralized outpatient opioid agonist therapy clinics and two community care centers; standard treatment was delivered in internal medicine outpatient clinics at centralized hospitals. Participants in the integrated treatment arm had a sustained virologic response of 93% compared to 73% for those in standard treatment arm. Psychological distress was assessed using SCL-10 prior to initiation of HCV treatment and 12 weeks after treatment completion. The mean SCL-10 score prior to HCV treatment was 2.2 (standard deviation [SD]: 0.7) for patients receiving integrated HCV treatment and 2.2 (SD: 0.8) for those receiving standard HCV treatment. Twelve weeks after the end of treatment, the mean SCL-10 score change was − 0.1 (− 0.3;0.0) in the integrated compared to the standard arm. Psychological distress did not substantially change during the treatment period and was not significantly different between the treatment arms.


Intervention -integrated HCV treatment
For participants in the integrated HCV treatment group, HCV assessments and follow-up were provided onsite at the OAT/CCC clinics.Those receiving OAT eligible for treatment were subsequently provided DAA along with their OAT medications, administrated by a nurse at the related OAT clinic.DAA medication and other HCV care were provided at the related CCC when the participant was not undergoing OAT.The differences between the delivery platforms in the two trial arms involve the following main aspects: No need to come for specific appointments at hospital and no need for travel for treatment in the integrated arm, less blood sampling in the integrated arm, integrated treatment provided by clinicians known the patients while standard care by hospital physicians not providing regular care to the patients, and less time used for follow-up of the treatment in the integrated arm.For a more detailed description of the methodology, see Supplementary files 2, 3.

Main outcome measure: Hopkins Symptom Checklist-10 (SCL-10)
We used the SCL-10, which is designed to record responses on 10 items to measure symptoms of mental health disorders and psychological distress 18 .Each item is scored on four dimensions from "not bothered at all" (item score = 1) to "extremely bothered" (item score = 4).To derive the mean item score, the scores on each item were summarized and divided by the number of items answered.

Characteristics at baseline
The baseline sociodemographic characteristics were similar between the arms.No significant differences (p > 0.05 for all comparisons) emerged between the arms for the baseline characteristics (Table 1).Achieving SVR did not significantly reduce the SCL-10 score 12 weeks after DAA treatment compared to those not achieving SVR (Supplementary files 4, 5).

The impact of integrated HCV treatment on psychological distress
Integrated HCV treatment did not significantly reduce the mean SCL-10 score from baseline to EOT12 compared with standard HCV treatment (ΔSCL-10 mean score: − 0.1, 95% confidence interval [CI] − 0.3; 0.0) (Table 2, Fig. 2).Substantial individual variations in mean SCL-10 score were observed over time across the treatment groups (Fig. 3).Per protocol analysis and sensitivity analyses showed similar results (Supplementary files 9, 10, 11, 12 and 13).

Discussion
This randomized controlled trial has showed that psychological distress was barely changed during the treatment of HCV and was not significantly different between integrated and standard treatment arms.Overall, and regardless of treatment approach, the symptom burden was substantial both at baseline and 12 weeks after DAA www.nature.com/scientificreports/treatment.A small non-significant trend of − 0.1 (ΔSCL-10 mean score, p = 0.091) reduction in psychological distress was observed with integrated HCV treatment compared to the standard arm.The symptom burden reported at EOT12 was substantial for participants in both the integrated and standard HCV treatment groups with mean SCL-10 scores of 2.2, which is far above the considered threshold for significant symptoms of psychological distress and symptoms of mental health disorder (mean SCL-10 score of 1.85).This is considerably higher compared to the general Norwegian population with mean SCL-10 score of 1.4 19 .This finding on the level of psychological distress in this population is consistent with our previous research on a large cohort of SUD patients.Furthermore, in a retrospective study from Australia 30% of the HCV infected patients reported a pre-existing mental health disorder of which 25% had depression, 2.6% bipolar disorder, 3.5% schizophrenia and 0.4% schizoaffective disorder 20 .Compared to interferon-based therapies, treatment with DAA has been associated with lower incidence of depressive symptoms 21 .In contrast to our findings, one other study of patients with HCV and co-occurring mental health disorders and SUD, showed significantly reduced symptoms of depression at EOT12 with DAA treatment, although differences in study design and methodology should make such interpretations cautious 22 .
Substantial intra-individual variations in mean SCL-10 score were observed from baseline to EOT 12 in both the integrated and standard treatment groups.In addition, these variations seem to go in both positive and negative directions and correspond with the findings in our cohort study on SCL-10 among 707 participants with SUD 3 .This is likely attributable to a range of external factors such as unstable living conditions, worrying debt situation, educational attainment, and severity of substance use, which also seems to be independent predictors of life-time symptoms of mental health disorders 23 .This indicates that, despite a strong trial design, a large intra-individual variation may reduce the analytic power.Finally, achieving SVR did not impact the mean SCL-10 score when adjusting for sociodemographic factors, intravenous injecting use, and any legal and illegal substance use in sensitivity analyses.
A major strength of this study is its design of individual randomization with balanced groups, which minimizes potential confounding.A limitation of this study might be the selection of outpatient clinics, where most participants received OAT, affecting the generalizability of our results to non-OAT populations.The sample size Table 2. Linear mixed model of changes in mean SCL-10 scores from baseline to EOT12 for integrated HCV treatment (intention-to-treat) (N = 289).Legends: EOT12: 12 weeks after the end of HCV treatment; SCL-10: The Hopkins Symptoms checklist-10; SVR: Sustained virological response.The table displays a linear mixed model analysis (Restricted Maximum Likelihood) regression of the impact of integrated HCV treatment on changes in mean SCL-10 scores (Δ mean SCL-10 score) from baseline to EOT12 (intention-to-treat analysis).The mean SCL-10 score ranged from 1 "not bothered at all" to 4 "extremely bothered".www.nature.com/scientificreports/may also be too low to observe a potentially significant difference between the arms.Moreover, both groups had a huge intraindividual variation in SCL-10 score from baseline to EOT12.This led to high variances and reduced statistical power in the analyses, which could hide significant differences between the groups.Another limitation is that 23% in the integrated treatment group and 38% in the standard treatment group were loss-to-follow-up of the SCL-10 assessments at EOT12, which may make the findings more uncertain.Sensitivity analyses without estimated data were performed to consider the impact of estimated values between the groups.Still, compared to the analyses with estimated data, no significant differences in SCL-10 scores between the groups were found.Furthermore, due to system and individual delays and changes in national guidelines for HCV treatment during the study period, the SCL-10 assessments were not conducted in exact concurrence with HCV treatment initiation and EOT12.This may have affected the results.

Conclusion
This randomized controlled trial showed that integrated HCV treatment is unlikely to have substantial co-benefits related to psychological distress within a 12-week timeframe of the study.Nevertheless, there may be subgroups who might benefit from an integrated care approach more than others, in addition to the benefits of facilitated HCV treatment initiation with implications for potential future somatic complications and improved quality of life, emphasizes the importance of integrated treatment approaches in people with substance use disorders.

Figure 2 .
Figure 2. A linear prediction of changes in mean SCL-10 scores from baseline to EOT12 (intention-to-treat analysis) (n = 289).EOT12: 12 weeks after the end of HCV treatment; SCL-10: Hopkins symptom checklist-10; HCV: Hepatitis C virus.The figure displays the linear prediction (fixed portion) including 95% confidence intervals of the mean SCL-10 score (Δ mean SCL-10 score) at baseline and from baseline (prior to HCV treatment) to EOT12 for integrated and standard HCV treatment groups.A Δmean SCL-10 score < 0 indicates improvement, while a Δmean SCL-10 score > 0 indicates impairing of the SCL-10 score from baseline to EOT12.The mean SCL-10 score ranged from 1 "not bothered at all" to 4 "extremely bothered".

Figure 3 .
Figure 3. Pen's parades of the mean SCL-10 scores at baseline and EOT12 (n = 289).Legends: EOT12: 12 weeks after the end of HCV infection treatment; HCV: Hepatitis C virus; SCL-10: Hopkins symptom checklist-10.The figures display participants who received integrated and standard HCV treatment.The graphs demonstrate the mean SCL-10 scores at baseline/prior to the HCV treatment and EOT12.A total of 23% (n = 33) in the integrated HCV treatment group and 38% (n = 56) in the standard HCV treatment group had no SCL-10 measurement at EOT12.The red line represents the SCL-10 mean scores at baseline when the participants are in sorted order by mean SCL-10 scores (from highest (left) to lowest (right) score).The blue spikes demonstrate the mean SCL-10 score at EOT12.The length of the spikes mark the changes in the mean SCL-10 score from baseline to EOT12.Participants without spikes did not complete SCL-10 assessment at EOT12.The dotted line represents the cut-off value of 1.85 indicating substantial mental health distress.The mean SCL-10 score ranged from 1 (not bothered at all) to 4 (extremely bothered).

Mean SCL-10 scores at baseline and 12 weeks after the end of treatment
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Table 1 .
Characteristics at baseline (n (%)).*None basic characteristics were significantly different, comparing the integrated treatment group to the standard treatment group, with a significance level of 0.05.Legends: IQR: Interquartile range; kPa: Kilopascal; a Unstable housing was defined as living in a homeless shelter, with family or friends, or on the street during the 30 days leading up to the first health assessment (baseline); b Frequent drug use was defined as using substance at least weekly during the 12 months leading up to the first health assessment (baseline).The table displays the sociodemographic and clinical characteristics of participants randomly assigned to integrated and standard HCV treatment groups.Vol.:(0123456789) Scientific Reports | (2024) 14:816 | https://doi.org/10.1038/s41598-024-51336-9